Antimicrobial drugs
By
Prof. Dr. Asem Shehabi and Dr. Suzan
Matar
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Introduction
 The use of antimicrobial drugs is successfully control
the majority of bacterial, parasitical, fungal infections
which affect human and animals.
 Sulfonamide 1934 chemical drug, Penicillin G 1941
obtained from Penicillium notatum..Natural drug
 Aminoglycosides (Streptomycin, Kanamycin)1946..
Natural drugs from soil bacteria Actinomycetes group.
 At present about 100 antimicrobial drugs of different
classes are available for use in humans.
 Clinically effective antimicrobial agents should exhibit
selective toxicity toward the bacterium not the host..
Few Side Effects.. Have good pharmacokinetics.
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General Antimicrobial Effects
 Drugs kill actively growing microorganisms are
bactericidal.. Penicillins, Aminoglycosides
 Drugs that only inhibit the growth of microorganisms
are termed bacteriostatic.. Sulfonamides,
Chloramphenicol, Tetracyclines
 The decision to use a bactericidal / bacteriostatic
drug to treat infection depends entirely upon the type
& body site of infection, patients age, kidney–Liver
functions.. acute or chronic infection.
 Final elimination of the organisms/infection is
dependent upon host immune defense..phagocytic
activity & specific antibodies
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Action of Antimicrobial Drugs on Bacteria
 Antimicrobials are classified according to the range of
activity/spectrum against bacteria:
- Narrow : Vancomycin, Penicillin (G+ve bacteria)
- Moderate: (G-ve/G+ve ) Ampicillin, Amoxicillin,
- Broad : (G-ve/G+ve) Tetracylines, Chloramphenicol
- Special drugs: Antimycobacteria, Antianaerobic
bacteria, Anti-urinary tract infections.
 Antimicrobials affect specific on various bacterial
cellular targets: cell wall, plasma membrane,
nucleic acids, proteins synthesis.
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Inhibition Cell Wall-1
 Penicillins and other beta-lactams contain a
characteristic 4-membered beta-lactam ring. Penicillin
kills bacteria through binding of the beta-lactam ring to
Transpeptidase/ Penicillin binding protein(PBPs)..
inhibiting its cross-linking activity and preventing new
growing peptidoglycan.. Stop cell wall synthesis &
activation cell wall autolysins..Killing effects.
 1- Narrow spectrum; Penicillin G for intramuscular
use (1941). Oral Penicillin V 1944 ..Acid stable.
- Affects mainly G+ve aerobic & anaerobic bacteria
- Less G-ve facultative anaerobic.
- Streptococci, Staphylococci, anaerobic bacteria
(Bacteroides & Clostridia).
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Benzylpenicillin: 5-Thazolidine Ring
Cephalosporin: 6-Dihydrothiazine Ring
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 2- Moderate spectrum: Ampicillin, Amoxacillin
(1960s).. G+ve/G-ve.. All these B-lactam drugs are
susceptible to Penicillinases /ß-Lactamases actions.
 Amoxacillin+Clavulinic Acid (B-lactamase inhibitor)
Broad Spectrum.. Against mild Penicillinase-R.. For
Gram +ve & -ve
 3- Penicillinase-R drugs:
 Oxacillin, flucloxacillin,Methicillin (1960s)
developed against Staph-R to Penicillins-Ampicillin.
- Methicillin-R Staph. aureus (MRSA) Worldwide
distribution .. Resistant to all Beta-Lactams.
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Inhibition Cell Wall-3
 4- Cephalosporins: 4 Generations..1965-1990s..Oral,
IV, IM.
 1th (1960) Cephalexin, Cephradine, Broad spectrum..
 2th (70s) Cefoxitin, Cefuroxime, Broad spectrum..
 3th (80s) Ceftriaxone, Cefotaxime.. mainly G-ve
Enteric bacteria..but effective against some G+Ve
bacteria Streptococcus pneumoniae
 4th (90s) Cefepime.
- Mainly G-ve Enteric bacteria
- UTI, RTI, Intestinal, Blood sepsis, CSF infections..
- Not used against anaerobes
- Increased resistance Enterococcus group ( E. fecalis)
in human intestinal
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Penicillin drugs against mostly Gramnegative Bacteria-3
 Carbencillin, Piperacillin (1970s)
Carboxypenicillins used mainly against G-ve
Pseudomonas spp.
 Monobactam: Aztreonam.. G-ve Enteric
bacteria
 Carbapenems: imipenem & meropenem
(2000) Broad Spectrum, some are resist
Extended Spectrum B-Lactamases , used
against Serious Nosocomial Infection, Enteric
bacilli., P. aeruginosa, Acinetobacter spp. due
to Develop of extended beta-lactamases.
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Inhibition Cell Wall-5
 Resistance Development :
 All G-ve enteric bacteria especially
- E.coli, Klebsiella/Enterobacter spp., P.aeruginosa &
Acinetobacter spp.
- Develop rapidly resistance by mutation & Plasmid transfer ßlactamases genes..
- Extended ß-lactamases ( > 100 types).
- Altered Penicillin Binding Proteins.. inactive
- Spread mostly in hospitalized patients.
 Methicillin resistance in S. aureus is mediated by the mecA
gene … production PBP-2a
 Side Effects: Sensitization, Penicillin Allergy, Fever, Serum
Sickness, Nephritis, Anaphylactic Shock
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2- Inhibition of membrane integrity
 Polyenes: Colistin /Polymixen E
- Large circular molecule consisting of a
hydrophobic and hydrophilic region..
- Complex Cyclic Polypeptides
- Bactericida.. Used mostly
- against G-ve serious infection..
Multiresistant
- Pathogens, Acinetobacter &
Pseudomonas
- Wounds, systemic.
- Topical & Intravenous,
- Nephrotoxic
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3-Inhibition Protein Synthesis
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Bacterial Ribosomes composed 30s+50s=70s
Aminoglycosides:
Ireversibly bind to the 30S ribosome.. inhibit the 30S
initiation complex
(30S-mRNA-tRNA)
Bactericidal
Broad-spectrum of activity
Mainly used against G-ve
Not Anaerobes
Serious Infection
Hospital IV, IM,
Streptomycin, Amikacin, Gentamicin, Tobramycin
Side Effects: Nephrotoxicity, Ototoxicity - 8th cranial
nerve- hearing loss, blood-level monitoring .
Contraindication in pregnancy causing neonatal
deafness
Resistance: Production acetylate, phosphorylate,
adenylate enzymes
Chromosomal & plasmid resistance
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3-Inhibition Protein Synthesis
Tetracyclines: Mid1950s :
Bacteriostatic and broad Spectrum
Accumulate in cytoplasmic membrane
Inhibit essential enzymes
Prevent attachment of the amino-acyl tRNA to 30S
ribosome complex
Side effect: over growth of yeast ( Candida spp.)
Tetracyclines shouldn’t given pregnant women or
children under 8-year.. Oral, Topical
Develop of resistance by reduced active transport and
Active efflux pumps system within cell membrane
Doxcycline, Minocycline.. Cholera, Respiratory &
Genital Infection.. Mycoplasma, Chlamydia, Legionella
infections.. New introduced Tigecycline ..Intravenous
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 Chloramphenicol, Mid1950s :
- Bacteriostatic
- Acts by binding to the 50S ribosomal subunit and
blocking the formation of the peptide bond
- Broad Spectrum.. Intracellular bacteria
- Meningitis, Septicemia, Typhoid fever
- Highly Toxic.. Oral, Intravenous, Topical
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Macrolides
 Large lactone ring structure
ranged between 14- or 16-Carbon
membered rings
 Binds to the 50S ribosomal subunit
 Inhibits either peptidyltransferase
activity or translocation of peptide to
mRNA.
 Most widely used Macrolides ..
Erythromycin, Clarithromycin,
Azithromycin ( Long acting-12
- hours) Oral
Relatively non-toxic drugs,
Mostly active against Gram-positive/ Intracellular bacteria- Respiratory Infections.. G+ve Pneumonia, Diphtheria.., Streptococci- Staphylococcal , Mycoplasma, Chlamydia,
Legionella pneumophila Infections.
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B) Lincosamides/Clindamycin, Lincomycin : inhibits
protein synthesis.. Staphylococcus.. Streptococci..
Bones, Oral cavity.. Anaerobic Infections. * Common
cause Pseudomembranous colitis.. Serious bloody
diarrhea.. Due to increase growth anaerobic sporeforming Clostridium difficile in intestine.
 Vancomycin: Complex glycopeptide ..blocking
formation Cell wall.. used in treatment of serious, lifethreatening infections..Gram-positive bacteria..MRSA,
Cl.difficle .. Damage to the kidneys and to the hearing
 Fusidic acid:
- Fusidic acid inhibits protein synthesis, used
against staphylococcal skin infection(MRSA) ..
topical treatment.
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4-Inhibition Nucleic Acid Synthesis
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Nalidixic acid (Quinolone): Inhibit DNA Gyrase/
Prevent DNA Replication.. Bactericidial.
 Floroquinolones: (1980s-2000s).. inhibit DNA Gyrase &
transcription & replication . Bactericidal, Norfloxacin,
Ciprofloxacin, Levofloxacin , Ofloxacin..Broad spectrum.. More
G-ve than G+e Infections.. intracellular pathogens, Urinary
Tract, Pneumonia, Septicemia.. Resistance by altered DNA
gyrase.. Develop due to mutation during treatment.
- Nitrofurantoin : Damage DNA.. Bacteriostatic
- Both Naldixic acid & Nitrofurantoin mainly are active against
G-ve enteric bacteria..E.coli.. used in Urinary tract Infection.
 Rifamycin /Rifampin: binds to the RNA polymerase..
Prevent its transcription from DNA .. Bactericidal,
Mycobacteria.. Intracellular bacteria.. Chlamydia, Brucella,
Resistance due to change in RNA polymerase ß-subunit .
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Floroquinolone/Ciprofloxacin
2-Nalidixic Acid
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5-Inhibition Synthesis of Essential Metabolites
 Sulfa drugs / Sulfonamides :
Structure analogue to PABA.. Compete
with it .. Block folic acid synthesis..
Essential for nucleic acid synthesis
..Mammals don’t need PABA or its
analogs
- Bacteriostatic.. Now Rarely used alone,
Rapid develop Resistance by altered.
 Sulfamethoxazole-trimethoprim
- 5:1 concentration
(Cotrimoxazole/Bactrim)
- Combined effects/Synergism,
- Oral Broad Spectrum
- UTI, RTI
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 Antituberculosis Drugs:
 Inhibition Mycolic acid .. Part of Mycobacterial Cell
Wall.. Mycobacterium tuberculosis.
- Isoniazid (INH), Ethambutol, Cycloserine,
Rifampin, Streptomycin.. oral & injectable
forms
- 3-12 months treatment by combination 2-3 drugs
Rapid Resistance develop if single drug used alone
MDR-TB) observed in the early 1990s
- Treatment of MR-tuberculosis requires 1-2 years.
 Metronidazol/
 inhibits nucleic acid synthesis by disrupting the
DNA of microbial cells. Active against most
Anaerobic Bacteria.. Oral & intravenous..Bacteria
develop slowly resistance
 Anti-protozoa
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Antibiotic Susceptibility Tests
 Laboratory Antibiotic Susceptibility Tests:
 Culture, Isolation, Identification of Bacteria from
clinical specimen as pure E. coli, S. aureus,
 Testing of only one pure fresh bacteria culture on
Mueller-Hinton Broth & Agar.. Disk Diffusion test ..
Measure inhibition zone after 24 hrs incubation 37oC
 Minimal Inhibitory Concentration (MIC/ug/ml) .. E-test
consists of a strip containing an exponential gradient of
one antibiotic(1-2-4-8-16-32-64-128-256) ug/ml
 Lab Report: Susceptible isolates (S) .. Intermediate
susceptible (IS).. Resistant (R)
 Multi-resistant.. Resistance to >2 antibiotic classes.
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Antibiotic Disc -Test
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Antibiotic E-test (MIC-mg/ml)
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Alarming of antimicrobial resistance
- All antimicrobial drugs in low/high doses can alter
the microbial body flora slowly or rapidly over time.
- Antibiotics have progressive selective pressure on
microorganisms in Human, Animals, Environment.
- Resistance is becoming a serious problem
Worldwide.. more commensal /pathogenic
microorganisms ( Bacteria, Yeast, Viruses) are
become untreatable with commonly used
antimicrobials.
- Development of bacterial resistance is increased
by overuse/ misuse of antimicrobials in medicine &
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agriculture and misuse by general population.
Antimicrobial Resistance
 Superbugs/MDR bacteria are now killing Thousands
of Patients over the world.
 Antimicrobial resistance is one the most serious public
health issues of our time (WHO,2014)
 Acinetobacter spp., Pseudomonas spp., E.coli, Klebsiella
pneumoniae, MR-staphylococci (MRSA), Va-R Enterococcus,
MR-Mycobacteria spp… High Mortality & High Treatment
Cost .
 Antibacterial resistance mechanism: Extended Spectrum βlactamases, ( ESBLs) more than 200 types, Efflux pumps,
mutations in cell membrane porins, modifying enzymes and
binding site mutations in Ribosomes. Horizontal transfer of
combined resistance by plasmids..results Develop multidrug
resistance.. Mostly Not Reversible.
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